New insights into fibrotic signaling in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) mostly occurs in the background of liver fibrosis, and activated hepatic stellate cells (HSCs) exist in HCC tissues and adjacent tissues. HSC activation is involved throughout the development of HCC precancerous lesions, which has gradually attracted the attention of related researchers. In addition, HCC can promote the activation of HSCs, which in turn accelerates the occurrence and development of HCC by promoting tumor angiogenesis. In this review, we reviewed 264 studies from PubMed and ScienceDirect to summarize and analyze current significant fibrotic signaling in HCC. As a result, we found 10 fibrotic signaling pathways that are closely related to the activation, proliferation, invasion, migration, and promotion of apoptosis of HCC cells. In addition, we found that crosstalk between various fibrotic signaling pathways of HCC, hypoxia-induced energy metabolic reprogramming of HCC cells, matrix stiffness and stemness of HCC cells, and ferroptosis of HCC cells and HSCs are the latest research hotspots. Furthermore, related drugs that have been found to target these 10 fibrotic signaling pathways of HCC are listed. Our study provides a new reference for developing anti-HCC drugs

EPAC activation inhibits acetaldehyde-induced activation and proliferation of hepatic stellate cell via Rap1

Hepatic stellate cells (HSCs) activation represents an essential event during alcoholic liver fibrosis (ALF). Previous studies have demonstrated that the rat HSCs could be significantly activated after exposure to 200 μM acetaldehyde for 48 h, and the cAMP/PKA signaling pathways were also dramatically upregulated in activated HSCs isolated from alcoholic fibrotic rat liver. Exchange protein activated by cAMP (EPAC) is a family of guanine nucleotide exchange factors (GEFs) for the small Ras-like GTPases Rap, and is being considered as a vital mediator of cAMP signaling in parallel with the principal cAMP target protein kinase A (PKA). Our data showed that both cAMP/PKA and cAMP/EPAC signaling pathways were involved in acetaldehyde-induced HSCs. Acetaldehyde could reduce the expression of EPAC1 while enhancing the expression of EPAC2. The cAMP analog Me-cAMP, which stimulates the EPAC/Rap1 pathway, could significantly decrease the proliferation and collagen synthesis of acetaldehyde-induced HSCs. Furthermore, depletion of EPAC2, but not EPAC1, prevented the activation of HSC measured as the production of α-SMA and collagen type I and III, indicating that EPAC1 appears to have protective effects on acetaldehyde-induced HSCs. Curiously, activation of PKA or EPAC perhaps has opposite effects on the synthesis of collagen and α-SMA, EPAC activation by Me-cAMP increased the levels of GTP-bound (activated) Rap1 while PKA activation by Phe-cAMP had no significant effects on such binding. These results suggested that EPAC activation could inhibit the activation and proliferation of acetaldehyde-induced HSCs via Rap1.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Comprehensive genomic signature of pyroptosis-related genes and relevant characterization in hepatocellular carcinoma

Background Currently, the most predominant type of liver cancer is hepatocellular carcinoma (HCC), which is also the fourth leading cause of cancer-related death in the global population. Pyroptosis is an emerging form of cell death that affects the prognosis of cancer patients by modulating tumor cell migration, proliferation and invasion. However, the evaluation of pyroptosis in the prognosis of HCC is still insufficient. Methods A total of 365 HCC patients from the TCGA-LIHC cohort were classified into two distinct subtypes using consensus clustering of pyroptosis-related genes (PRGs). Following univariate Cox analysis of differentially expressed genes between subtypes, we established a prognostic model (PRGs-score, PRGS) by LASSO Cox analysis. We further tested the predictive power of the prognostic model in the ICGC (LIRI-JP) and GEO (GSE14520) cohorts. The tumor microenvironment (TME) was studied using the CIBERSORT. The enrichment scores for immune cells and immune functions in low- and high-PRGS groups were assessed using ssGSEA. The IMvigor210 cohort was used to investigate the immunotherapy efficacy. Furthermore, we validated the expression of prognostic genes in PRGS by RT-qPCR in vitro. Results The subtyping of HCC based on PRGs exhibited distinct clinical characteristics. We developed a prognostic model PRGS by differentially expressed genes between different subtypes. The results showed that PRGS could well forecast the survival of HCC patients in different cohorts and was associated with the immune microenvironment. Moreover, PRGS was considered to be an independent prognostic risk factor and superior to other pyroptosis-related signatures. Low-PRGS implied greater immune cell infiltration and better overall survival with immunotherapy. The results of RT-qPCR also showed that prognostic genes were significantly dysregulated in HCC. Conclusions PRGS has promising application in forecasting the prognosis of HCC patients, and its relationship with the immune microenvironment provides a basis for the subsequent treatment and research of HCC

Matrix metalloproteinases induce extracellular matrix degradation through various pathways to alleviate hepatic fibrosis

Liver fibrosis is the common consequence of various chronic liver injuries and is mainly characterized by the imbalance between the production and degradation of extracellular matrix, which leads to the accumulation of interstitial collagen and other matrix components. Matrix metalloproteinases (MMPs) and their specific inhibitors, that is, tissue inhibitors of metalloproteinases (TIMPs), play a crucial role in collagen synthesis and lysis. Previous in vivo and in vitro studies of our laboratory found repressing extracellular matrix (ECM) accumulation by restoring the balance between MMPs and TIMPs can alleviate liver fibrosis. We conducted a review of articles published in PubMed and Science Direct in the last decade until February 1, 2023, which were searched for using these words “MMPs/TIMPs” and “Hepatic Fibrosis.” Through a literature review, this article reviews the experimental studies of liver fibrosis based on MMPs/TIMPs, summarizes the components that may exert an anti-liver fibrosis effect by affecting the expression or activity of MMPs/TIMPs, and attempts to clarify the mechanism of MMPs/TIMPs in regulating collagen homeostasis, so as to provide support for the development of anti-liver fibrosis drugs. We found the MMP-TIMP-ECM interaction can result in better understanding of the pathogenesis and progression of hepatic fibrosis from a different angle, and targeting this interaction may be a promising therapeutic strategy for hepatic fibrosis. Additionally, we summarized and analyzed the drugs that have been found to reduce liver fibrosis by changing the ratio of MMPs/TIMPs, including medicine natural products

Caffeine inhibits the activation of hepatic stellate cells induced by acetaldehyde via adenosine A2A receptor mediated by the cAMP/PKA/SRC/ERK1/2/P38 MAPK signal pathway.

Hepatic stellate cell (HSC) activation is an essential event during alcoholic liver fibrosis. Evidence suggests that adenosine aggravates liver fibrosis via the adenosine A2A receptor (A2AR). Caffeine, which is being widely consumed during daily life, inhibits the action of adenosine. In this study, we attempted to validate the hypothesis that caffeine influences acetaldehyde-induced HSC activation by acting on A2AR. Acetaldehyde at 50, 100, 200, and 400 μM significantly increased HSC-T6 cells proliferation, and cell proliferation reached a maximum at 48 h after exposure to 200 μM acetaldehyde. Caffeine and the A2AR antagonist ZM241385 decreased the cell viability and inhibited the expression of procollagen type I and type III in acetaldehyde-induced HSC-T6 cells. In addition, the inhibitory effect of caffeine on the expression of procollagen type I was regulated by A2AR-mediated signal pathway involving cAMP, PKA, SRC, and ERK1/2. Interestingly, caffeine's inhibitory effect on the expression of procollagen type III may depend upon the A2AR-mediated P38 MAPK-dependent pathway.Caffeine significantly inhibited acetaldehyde-induced HSC-T6 cells activation by distinct A2AR mediated signal pathway via inhibition of cAMP-PKA-SRC-ERK1/2 for procollagen type I and via P38 MAPK for procollagen type III

sj-docx-1-inq-10.1177_00469580231151783 – Supplemental material for Substantial Increase in Accessibility to Essential Anticancer Medicines in Anhui, China: A Longitudinal Study

Supplemental material, sj-docx-1-inq-10.1177_00469580231151783 for Substantial Increase in Accessibility to Essential Anticancer Medicines in Anhui, China: A Longitudinal Study by Rixiang Xu, Shuting Li, Tingyu Mu, Xuefeng Xie, Caiming Xu and Xiongwen Lv in INQUIRY: The Journal of Health Care Organization, Provision, and Financing</p

Pyrrolidine Dithiocarbamate (PDTC) Attenuates Cancer Cachexia by Affecting Muscle Atrophy and Fat Lipolysis

Cancer cachexia is a kind of whole body metabolic disorder syndrome accompanied with severe wasting of muscle and adipose tissue. NF-κB signaling plays an important role during skeletal muscle atrophy and fat lipolysis. As an inhibitor of NF-κB signaling, Pyrrolidine dithiocarbamate (PDTC) was reported to relieve cancer cachexia; however, its mechanism remains largely unknown. In our study, we showed that PDTC attenuated cancer cachexia symptom in C26 tumor bearing mice models in vivo without influencing tumor volume. What’s more, PDTC inhibited muscle atrophy and lipolysis in cells models in vitro induced by TNFα and C26 tumor medium. PDTC suppressed atrophy of myotubes differentiated from C2C12 by reducing MyoD and upregulating MuRF1, and preserving the expression of perilipin as well as blocking the activation of HSL in 3T3-L1 mature adipocytes. Meaningfully, we observed that PDTC also inhibited p38 MAPK signaling besides the NF-κB signaling in cancer cachexia in vitro models. In addition, PDTC also influenced the protein synthesis of skeletal muscle by activating AKT signaling and regulated fat energy metabolism by inhibiting AMPK signaling. Therefore, PDTC primarily influenced different pathways in different tissues. The study not only established a simple and reliable screening drugs model of cancer cachexia in vitro but also provided new theoretical basis for future treatment of cancer cachexia

Effect of caffeine and A2AR modulators on the acetaldehyde-induced HSC-T6 cells proliferation.

<p>(<b>A</b>) HSC-T6 cells were treated with caffeine (final concentration of caffeine was 0.5, 1, 2, 4, 8 mM, respectively) at the indicated times (24h, 48h, 72h). (<b>B</b>) HSC-T6 cells were treated with ZM24138 (final concentration of ZM24138 was 1, 10, 100, 1000, 10000 nM, respectively) at the indicated times (24h, 48h). (<b>C</b>) HSC-T6 cells were treated with CGS21680 (final concentration of CGS21680 was 1, 10, 100, 1000, 10000 nM, respectively) at the indicated times (24h, 48h). Cell viability was determined by MTT assay. Each column represents the mean±S.D. of six separate experiments. ^△△ indicates P<0.01 versus control group. ^* indicates P<0.05, ^** indicates P<0.01 versus model group (acetaldehyde 200 μM only).</p

Effect of caffeine and A2AR modulators on the mRNA Expression of PKA in acetaldehyde-induced HSC-T6 cells.

<p>HSC-T6 cells were treated with 200 μM acetaldehyde, 4 mM caffeine, 1 μM CGS21680, 1 μM ZM241385, 1 μM CGS21680 plus 4 mM caffeine or 1 μM CGS21680 plus 1 μM ZM241385 for 48h before harvesting and measurement of PKA in the cells as described. Data are expressed as the mean ±S.D. (n = 3). ^△△ indicates P<0.01 versus control group. ^* indicates P<0.05, ^** indicates P<0.01 versus model group (acetaldehyde 200 μM only). ^# indicates P<0.05 versus caffeine group. ⁺ indicates P<0.05 versus ZM241385 group. ^&& indicates P<0.01 versus CGS21680 group.</p

Effect of caffeine and A2AR modulators on the phosphorylation of SRC, ERK1/2, and P38 MAPK pathway in acetaldehyde-induced HSC-T6 cells.

<p>(A) SRC Kinase. (B) ERK1/2 MAPK. (C) P38 MAPK. HSC-T6 cells were treated with 200 μM acetaldehyde, 4 mM caffeine, 1 μM CGS21680, 1 μM ZM241385, 1 μM CGS21680 plus 4 mM caffeine or 1 μM CGS21680 plus 1 μM ZM241385 for 48h before harvesting and measurement of proteins expression in cells as described. Data are expressed as the mean ±S.D. (n = 3). ^△△ indicates P<0.01 versus control group. ^* indicates P<0.05, ^**indicates P<0.01 versus model group (acetaldehyde 200 μM only). ^# indicates P<0.05, ^## indicates P<0.01 versus caffeine group. ⁺ indicates P<0.05, ⁺⁺ indicates P<0.01 versus ZM241385 group. ^&& indicates P<0.01 versus CGS21680 group. a: Control, b: Model, c: Caffeine, d: ZM241385, e: CGS21680, f: Caffeine+CGS21680, g: ZM241385+CGS21680.</p